Describing the content of trial recruitment interventions using the TIDieR reporting checklist: a systematic methodology review.

BACKGROUND: Recruiting participants to clinical trials is an ongoing challenge, and relatively little is known about what recruitment strategies lead to better recruitment. Recruitment interventions can be considered complex interventions, often involving multiple components, targeting a variety of groups, and tailoring to different groups. We used the Template for Intervention Description and Replication (TIDieR) reporting checklist (which comprises 12 items recommended for reporting complex interventions) to guide the assessment of how recruitment interventions are described. We aimed to (1) examine to what extent we could identify information about each TIDieR item within recruitment intervention studies, and (2) observe additional detail for each item to describe useful variation among these studies. METHODS: We identified randomized, nested recruitment intervention studies providing recruitment or willingness to participate rates from two sources: a Cochrane review of trials evaluating strategies to improve recruitment to randomized trials, and the Online Resource for Research in Clinical triAls database. First, we assessed to what extent authors reported information about each TIDieR item. Second, we developed descriptive categorical variables for 7 TIDieR items and extracting relevant quotes for the other 5 items. RESULTS: We assessed 122 recruitment intervention studies. We were able to extract information relevant to most TIDieR items (e.g., brief rationale, materials, procedure) with the exception of a few items that were only rarely reported (e.g., tailoring, modifications, planned/actual fidelity). The descriptive variables provided a useful overview of study characteristics, with most studies using various forms of informational interventions (55%) delivered at a single time point (90%), often by a member of the research team (59%) in a clinical care setting (41%). CONCLUSIONS: Our TIDieR-based variables provide a useful description of the core elements of complex trial recruitment interventions. Recruitment intervention studies report core elements of complex interventions variably; some process elements (e.g., mode of delivery, location) are almost always described, while others (e.g., duration, fidelity) are reported infrequently, with little indication of a reason for their absence. Future research should explore whether these TIDieR-based variables can form the basis of an approach to better reporting of elements of successful recruitment interventions.

Patient and public involvement in pragmatic trials: online survey of corresponding authors of published trials.

BACKGROUND: There are few data on patient and public involvement (PPI) in pragmatic trials. We aimed to describe the prevalence and nature of PPI within pragmatic trials, describe variation in prevalence of PPI by trial characteristics and compare prevalence of PPI reported by trial authors to that reported in trial publications. METHODS: We applied a search filter to identify pragmatic trials published from 2014 to 2019 in MEDLINE. We invited the corresponding authors of pragmatic trials to participate in an online survey about their specific trial. RESULTS: Of 3163 authors invited, 2585 invitations were delivered, 710 (27.5%) reported on 710 unique trials and completed the survey; 334 (47.0%) conducted PPI. Among those who conducted PPI, for many the aim was to increase the research relevance (86.3%) or quality (76.5%). Most PPI partners were engaged at protocol development stages (79.1%) and contributed to the co-design of interventions (70.9%) or recruitment or retention strategies (60.5%). Patient and public involvement was more common among trials involving children, trials conducted in the United Kingdom, cluster randomized trials, those explicitly labelled as "pragmatic" in the study manuscript, and more recent trials. Less than one-quarter of trials (22.8%) that reported PPI in the survey also reported PPI in the trial manuscript. INTERPRETATION: Nearly half of trialists in this survey reported conducting PPI and listed several benefits of doing so, but researchers who did not conduct PPI often cited a lack of requirement for it. Patient and public involvement appears to be significantly underreported in trial publications. Consistent and standardized reporting is needed to promote transparency about PPI methods, outcomes, challenges and benefits.

Health equity considerations in pragmatic trials in Alzheimer's and dementia disease: Results from a methodological review.

Introduction: To improve dementia care delivery for persons across all backgrounds, it is imperative that health equity is integrated into pragmatic trials. Methods: We reviewed 62 pragmatic trials of people with dementia published 2014 to 2019. We assessed health equity in the objectives; design, conduct, analysis; and reporting using PROGRESS-Plus which stands for Place of residence, Race/ethnicity, Occupation, Gender/sex, Religion, Education, Socioeconomic status, Social capital, and other factors such as age and disability. Results: Two (3.2%) trials incorporated equity considerations into their objectives; nine (14.5%) engaged with communities; 4 (6.5%) described steps to increase enrollment from equity-relevant groups. Almost all trials (59, 95.2%) assessed baseline balance for at least one PROGRESS-Plus characteristic, but only 10 (16.1%) presented subgroup analyses across such characteristics. Differential recruitment, attrition, implementation, adherence, and applicability across PROGRESS-Plus were seldom discussed. Discussion: Ongoing and future pragmatic trials should more rigorously integrate equity considerations in their design, conduct, and reporting. Highlights: Few pragmatic trials are explicitly designed to inform equity-relevant objectives.Few pragmatic trials take steps to increase enrollment from equity-relevant groups.Disaggregated results across equity-relevant groups are seldom reported.Adherence to existing tools (e.g., IMPACT Best Practices, CONSORT-Equity) is key.

Supporting Trial Participation in People with the Huntington's Gene: A Patient-Centered, Theory-Guided Survey of Barriers and Enablers.

BACKGROUND: Under-recruitment regularly impedes clinical trials, leading to wasted resources and opportunity costs. Methods for designing trial participation strategies rarely consider behavior change theory. OBJECTIVE: Informed by the Theoretical Domains Framework, we identified factors important to participating in Huntington's disease research and provide examples of how such a theory-informed approach can make specific suggestions about how to design targeted recruitment strategies. METHODS: We identified a range of trial participation barriers and enablers based on interviews of key informants and implemented an online survey of members of the Huntington's disease community, asking them to rate the extent to which different factors would affect likelihood to participate in a generic Huntington's disease trial. RESULTS: From 4,195 members, we received 323 responses and 243 completed surveys (323/4,195 or 8% participation, 243/323 or 75% completion). Respondents endorsed 9 barriers and 23 enablers relevant to trial participation. Most frequently endorsed barriers were travel to the study site (69%), worry about unknown side effects (65%), trial documents being difficult to understand (64%), and participation affecting other activities (49%). Enablers included optimism about likelihood of trial participation leading to a cure (98%), helping others (98%), contributing to science (97%), and having helpful people available to help with the participation decision (89%). CONCLUSION: Our theory-informed survey to identify barriers to and enablers of Huntington's disease trial participation identified 32 factors, from 13 theoretical domains relevant to trial participation, and suggests effective approaches for improving trial participation and patient experience.

An analysis of published trials found that current use of pragmatic trial labels is uninformative.

OBJECTIVES: Randomized trials labelled as "pragmatic" are attractive to funders, patients, and clinicians as the label implies that the results are directly applicable to clinical care. We examined how authors justify use of the label (e.g., by referring to one or more PRECIS [PRagmatic Explanatory Continuum Indicator Summary]-2 domains). STUDY DESIGN AND SETTING: We reviewed primary trial reports published 2014-2019, registered in ClinicalTrials.gov and using the pragmatic label anywhere in the report. RESULTS: Among 415 trials, the label was justified by reference to at least one design element in 282 (68.0%); of these, 240 (85.1%) referenced trial characteristics that can be mapped to one or more of the PRECIS-2 domains, most commonly eligibility (91, 32.3%), setting (90, 31.9%), flexibility delivery (89, 31.6%), and organization (75, 26.6%); 42 (14.9%) referenced characteristics that are not PRECIS-2 domains, most commonly type of intervention/comparator (48, 17%), recruitment without consent (22, 7.8%), routinely collected data (22, 7.8%), and cluster randomization (20, 7.1%). Most reports referenced only one or two design elements. Overall, 9/415 (2.2%) provided PRECIS wheels. CONCLUSION: Current use of pragmatic labels is uninformative. Authors should clarify the decision the trial is intended to support and include a PRECIS-2 table to make the design transparent.

Ethical considerations within pragmatic randomized controlled trials in dementia: Results from a literature survey.

Introduction: This review aims to describe the landscape of pragmatic randomized controlled trials (RCTs) in the context of Alzheimer's disease (AD) and related dementias with respect to ethical considerations. Methods: Searches of MEDLINE were performed from January 2014 until April 2019. Extracted information included: trial setting, interventions, data collection, study population, and ethical protections (including ethics approvals, capacity assessment, and informed consent). Results: We identified 62 eligible reports. More than two-thirds (69%) included caregivers or health-care professionals as research participants. Fifty-eight (94%) explicitly identified at least one vulnerable group. Two studies did not report ethics approval. Of 57 studies in which patients were participants, 55 (96%) reported that consent was obtained but in 37 studies (67%) no mention was made regarding assessment of the patients' capacity to consent to research participation. Discussion: Few studies reported protections implemented when vulnerable participants were included. Shortcomings remain when reporting consent approaches and capacity assessment.

A review identified challenges distinguishing primary reports of randomized trials for meta-research: A proposal for improved reporting.

Meta-research is the discipline of studying research itself. A core investigative tool in meta-research is the use of systematic or scoping reviews to study the characteristics, methods and reporting of primary research studies. In the context of identifying eligible publications for methodological reviews of randomized controlled trials (RCTs), a challenge is to efficiently distinguish the primary trial report - which reports results for the primary outcome - from other types of reports, including design papers and secondary or supplementary analyses, or what we collectively refer to as non-primary reports. This may not be a straightforward task and may contribute to inefficiencies in the review process. Here, we draw on our recent methodological review of over 13,000 records to identify primary reports of pragmatic RCTs. We offer recommendations to improve the reporting of RCTs to facilitate more efficient identification of primary trial reports. We suggest that future updates to existing CONSORT guidelines include consideration of multiple trial reports and recommendations to clarify the primary or non-primary nature of each report. Our recommendations, together with improved adherence to inclusion of the trial registration number in the abstract and citation of a protocol or previously published primary report, would facilitate the conduct of methodological reviews.

Reporting of and explanations for under-recruitment and over-recruitment in pragmatic trials: a secondary analysis of a database of primary trial reports published from 2014 to 2019.

OBJECTIVES: To describe the extent to which pragmatic trials underachieved or overachieved their target sample sizes, examine explanations and identify characteristics associated with under-recruitment and over-recruitment. STUDY DESIGN AND SETTING: Secondary analysis of an existing database of primary trial reports published during 2014-2019, registered in ClinicalTrials.gov, self-labelled as pragmatic and with target and achieved sample sizes available. RESULTS: Of 372 eligible trials, the prevalence of under-recruitment (achieving <90% of target sample size) was 71 (19.1%) and of over-recruitment (>110% of target) was 87 (23.4%). Under-recruiting trials commonly acknowledged that they did not achieve their targets (51, 71.8%), with the majority providing an explanation, but only 11 (12.6%) over-recruiting trials acknowledged recruitment excess. The prevalence of under-recruitment in individually randomised versus cluster randomised trials was 41 (17.0%) and 30 (22.9%), respectively; prevalence of over-recruitment was 39 (16.2%) vs 48 (36.7%), respectively. Overall, 101 025 participants were recruited to trials that did not achieve at least 90% of their target sample size. When considering trials with over-recruitment, the total number of participants recruited in excess of the target was a median (Q1-Q3) 319 (75-1478) per trial for an overall total of 555 309 more participants than targeted. In multinomial logistic regression, cluster randomisation and lower journal impact factor were significantly associated with both under-recruitment and over-recruitment, while using exclusively routinely collected data and educational/behavioural interventions were significantly associated with over-recruitment; we were unable to detect significant associations with obtaining consent, publication year, country of recruitment or public engagement. CONCLUSIONS: A clear explanation for under-recruitment or over-recruitment in pragmatic trials should be provided to encourage transparency in research, and to inform recruitment to future trials with comparable designs. The issues and ethical implications of over-recruitment should be more widely recognised by trialists, particularly when designing cluster randomised trials.

Methodological challenges in pragmatic trials in Alzheimer's disease and related dementias: Opportunities for improvement.

BACKGROUND AND AIMS: We need more pragmatic trials of interventions to improve care and outcomes for people living with Alzheimer's disease and related dementias. However, these trials present unique methodological challenges in their design, analysis, and reporting-often, due to the presence of one or more sources of clustering. Failure to account for clustering in the design and analysis can lead to increased risks of Type I and Type II errors. We conducted a review to describe key methodological characteristics and obtain a "baseline assessment" of methodological quality of pragmatic trials in dementia research, with a view to developing new methods and practical guidance to support investigators and methodologists conducting pragmatic trials in this field. METHODS: We used a published search filter in MEDLINE to identify trials more likely to be pragmatic and identified a subset that focused on people living with Alzheimer's disease or other dementias or included them as a defined subgroup. Pairs of reviewers extracted descriptive information and key methodological quality indicators from each trial. RESULTS: We identified N = 62 eligible primary trial reports published across 36 different journals. There were 15 (24%) individually randomized, 38 (61%) cluster randomized, and 9 (15%) individually randomized group treatment designs; 54 (87%) trials used repeated measures on the same individual and/or cluster over time and 17 (27%) had a multivariate primary outcome (e.g. due to measuring an outcome on both the patient and their caregiver). Of the 38 cluster randomized trials, 16 (42%) did not report sample size calculations accounting for the intracluster correlation and 13 (34%) did not account for intracluster correlation in the analysis. Of the 9 individually randomized group treatment trials, 6 (67%) did not report sample size calculations accounting for intracluster correlation and 8 (89%) did not account for it in the analysis. Of the 54 trials with repeated measurements, 45 (83%) did not report sample size calculations accounting for repeated measurements and 19 (35%) did not utilize at least some of the repeated measures in the analysis. No trials accounted for the multivariate nature of their primary outcomes in sample size calculation; only one did so in the analysis. CONCLUSION: There is a need and opportunity to improve the design, analysis, and reporting of pragmatic trials in dementia research. Investigators should pay attention to the potential presence of one or more sources of clustering. While methods for longitudinal and cluster randomized trials are well developed, accessible resources and new methods for dealing with multiple sources of clustering are required. Involvement of a statistician with expertise in longitudinal and clustered designs is recommended.

Review of pragmatic trials found that multiple primary outcomes are common but so too are discrepancies between protocols and final reports.

OBJECTIVES: To describe prevalence of multiple primary outcomes, changes in primary outcomes and target sample sizes between protocols and final reports, and how issues of multiplicity are addressed in pragmatic trials. STUDY DESIGN AND SETTING: Individually randomized trials labeled as pragmatic, published 2014-2019 in MEDLINE and registered with ClinicalTrials.gov. RESULTS: We identified 262 final reports and located protocols for 159 (61%); primary outcomes were clearly reported in 145 (91%) protocols and 256 (98%) final reports. Thirty (19%) protocols and 38 (15%) final reports had multiple primary outcomes. Primary outcomes were present and identical in 128 (81%) matched protocol-final reports. Among 140 pairs with target sample sizes reported, 28 (20.0%) reduced their target sample size (mean 543 fewer participants per trial) and 16 (11.4%) increased it (mean 192 more participants per trial). Thirteen (29.5%) provided an explanation. Only 2 of 30 (7%) protocols and 4 of 38 (11%) final reports with co-primary outcomes explained how results would be interpreted in light of multiplicity; 21 of 30 (70%) protocols and 20 of 38 (53%) final reports accounted for co-primary outcomes in power calculations. CONCLUSION: Co-primary outcomes are common in pragmatic trials; improved transparency around design and analysis decisions involving co-primary outcomes is required.

Informed consent in pragmatic trials: results from a survey of trials published 2014-2019.

OBJECTIVES: To describe reporting of informed consent in pragmatic trials, justifications for waivers of consent and reporting of alternative approaches to standard written consent. To identify factors associated with (1) not reporting and (2) not obtaining consent. METHODS: Survey of primary trial reports, published 2014-2019, identified using an electronic search filter for pragmatic trials implemented in MEDLINE, and registered in ClinicalTrials.gov. RESULTS: Among 1988 trials, 132 (6.6%) did not include a statement about participant consent, 1691 (85.0%) reported consent had been obtained, 139 (7.0%) reported a waiver and 26 (1.3%) reported consent for one aspect (eg, data collection) but a waiver for another (eg, intervention). Of the 165 trials reporting a waiver, 76 (46.1%) provided a justification. Few (53, 2.9%) explicitly reported use of alternative approaches to consent. In multivariable logistic regression analyses, lower journal impact factor (p=0.001) and cluster randomisation (p<0.0001) were significantly associated with not reporting on consent, while trial recency, cluster randomisation, higher-income country settings, health services research and explicit labelling as pragmatic were significantly associated with not obtaining consent (all p<0.0001). DISCUSSION: Not obtaining consent seems to be increasing and is associated with the use of cluster randomisation and pragmatic aims, but neither cluster randomisation nor pragmatism are currently accepted justifications for waivers of consent. Rather than considering either standard written informed consent or waivers of consent, researchers and research ethics committees could consider alternative consent approaches that may facilitate the conduct of pragmatic trials while preserving patient autonomy and the public's trust in research.

Patient Partner Perspectives Regarding Ethically and Clinically Important Aspects of Trial Design in Pragmatic Cluster Randomized Trials for Hemodialysis.

BACKGROUND: Cluster randomized trials (CRTs) are trials in which intact groups such as hemodialysis centers or shifts are randomized to treatment or control arms. Pragmatic CRTs have been promoted as a promising trial design for nephrology research yet may also pose ethical challenges. While randomization occurs at the cluster level, the intervention and data collection may vary in a CRT, challenging the identification of research participants. Moreover, when a waiver of patient consent is granted by a research ethics committee, there is an open question as to whether and to what degree patients should be notified about ongoing research or be provided with a debrief regarding the nature and results of the trial upon completion. While empirical and conceptual research exploring ethical issues in pragmatic CRTs has begun to emerge, there has been limited discussion with patients, families, or caregivers of patients undergoing hemodialysis. OBJECTIVE: To explore with patients and families with experience of hemodialysis research the challenges raised by different approaches to designing pragmatic CRTs in hemodialysis. Specifically, their perceptions of (1) the use of a waiver of consent, (2) notification processes and information provided to participants, and (3) any other concerns about cluster randomized designs in hemodialysis. DESIGN: Focus group and interview discussions of hypothetical clinical trial designs. SETTING: Focus groups and interviews were conducted in-person or via videoconference or telephone. PARTICIPANTS: Patient partners in hemodialysis research, defined as patients with personal experience of dialysis or a family member who had experience supporting a patient receiving hemodialysis, who have been actively involved in discussions to advise a research team on the design, conduct, or implementation of a hemodialysis trial. METHODS: Participants were invited to participate in focus groups or individual discussions that were audio recorded with consent. Recorded interviews were transcribed verbatim prior to analysis. Transcripts were analyzed using a thematic analysis approach. RESULTS: Two focus groups, three individual interviews, and one interview involving a patient and family member were conducted with 17 individuals between February 2019 and May 2020. Participants expressed support for approaches that emphasized patient choice. Disclosure of patient-relevant risks and information were key themes. Both consent and notification processes served to generate trust, but bypassing patient choice was perceived as undermining this trust. Participants did not dismiss the option of a waiver of consent. They were, however, more restrictive in their views about when a waiver of consent may be acceptable. Patient partners were skeptical of claims to impracticability based on costs or the time commitments for staff. LIMITATIONS: All participants were from Canada and had been involved in the design or conduct of a trial, limiting the degree to which results may be extrapolated. CONCLUSIONS: Given the preferences of participants to be afforded the opportunity to decide about trial participation, we argue that investigators should thoroughly investigate approaches that allow participants to make an informed choice regarding trial participation. In keeping with the preference for autonomous choice, there remains a need to further explore how consent approaches can be designed to facilitate clinical trial conduct while meeting their ethical requirements. Finally, further work is needed to define the limited circumstances in which waivers of consent are appropriate.

CONTEXTE: Les essais randomisés en grappes (CRT ­ Cluster Randomized Trials) sont des essais dans lesquels des groupes intacts, comme des centers ou horaires d'hémodialyse, sont répartis aléatoirement dans des groupes traités ou témoins. Les CRT pragmatiques ont été présentés comme un modèle prometteur pour la recherche en néphrologie, mais susceptible de poser des défis sur le plan éthique. Bien que la répartition aléatoire ait lieu au niveau du groupe, les interventions et la collecte de données peuvent varier dans un CRT, ce qui peut complexifier l'identification des participants. Aussi, lorsque le comité d'éthique de la recherche accorde une dérogation au consentement des patients, une question ouverte se pose quant à savoir si, et dans quelle mesure, les patients devraient être informés de la recherche en cours ou recevoir un compte rendu sur la nature et les résultats de l'étude une fois celle-ci terminée. Alors que des recherches empiriques et conceptuelles explorant les questions éthiques dans les CRT pragmatiques commencent à poindre, peu de discussions ont eu lieu avec les patients sous hémodialyse, leurs familles ou leurs soignants. OBJECTIFS: Explorer les défis posés par différentes approches de conception des CRT pragmatiques en contexte d'hémodialyse avec des patients ayant de l'expérience en recherche sur l'hémodialyse et leurs familles. Plus précisément : connaître leur avis sur a) l'utilization d'une renonciation au consentement; b) les processus de notification et les renseignements fournis aux participants; et c) toute autre préoccupation concernant les CRT en contexte d'hémodialyse. TYPE D'ÉTUDE: Entrevues et groupes de discussion sur la conception d'essais cliniques hypothétiques. CADRE: Les groupes de discussion et les entrevues ont eu lieu en personne, par vidéoconférence ou par téléphone. PARTICIPANTS: Les patients partenaires de recherche en hémodialyse ­ définis comme des patients ayant une expérience personnelle en dialyze ou un membre de leur famille avec de l'expérience dans l'accompagnement d'un patient en hémodialyse ­ qui ont participé activement à des discussions pour conseiller une équipe de recherche sur la conception, la conduite ou la mise en œuvre d'une étude en hémodialyse. MÉTHODOLOGIE: Les participants ont été invités à participer à des discussions individuelles et des groupes de discussion enregistrés avec leur consentement. Les enregistrements ont été transcrits intégralement avant l'analyze et les transcriptions ont été analysées en utilisant une approche d'analyze thématique. RÉSULTATS: Deux groupes de discussion, trois entrevues individuelles et une entrevue avec un patient et un membre de sa famille ont été menés auprès de 17 personnes entre février 2019 et mai 2020. Les participants ont exprimé leur appui aux approches qui privilégient le choix des patients. La divulgation des risques et des renseignements concernant le patient était un thème clé. Les processus de consentement et de notification ont tous deux généré de la confiance, mais le fait de contourner le choix du patient a été perçu comme une atteinte à celle-ci. Les participants n'ont pas écarté l'option d'une renonciation au consentement, mais ont été plus restrictifs quant au moment où celle-ci serait acceptable. Les patients partenaires se sont montrés sceptiques quant aux allégations d'impraticabilité fondées sur les coûts ou l'engagement en temps pour le personnel. LIMITES: Tous les participants étaient canadiens et avaient participé à la conception ou à la conduite d'un essai, ce qui limite le degré d'extrapolation des résultats. CONCLUSION: Puisque les participants préfèrent avoir le choix de participer à une étude, nous pensons que les chercheurs devraient étudier attentivement les approches qui permettent aux participants de faire un choix éclairé en cette matière. Conformément à la préférence pour un choix autonome, il demeure nécessaire d'explorer plus profondément la façon dont les approches de consentement peuvent être conçues pour faciliter la conduite des essais cliniques tout en respectant leurs exigences éthiques. D'autres travaux sont nécessaires pour définir les rares circonstances où une renonciation au consentement serait appropriée.

Results from a Theory-Guided Survey to Support Breast Cancer Trial Participation: Barriers, Enablers, and What to Do about them.

BACKGROUND: Ensuring adequate, informed, and timely participation in clinical trials is a multifactorial problem. We have previously developed a systematic, tailorable survey development approach that is informed by theory, can identify barriers and enablers to participation, and can suggest recruitment strategies to address these issues. In this study, we surveyed subscribers to the Canadian Breast Cancer Network (CBCN) in order to identify a comprehensive list of theory-informed barriers and enablers relevant to participation in a hypothetical breast cancer trial. METHODS: We developed and conducted an online survey of breast cancer patients informed by the Theoretical Domains Framework and designed to determine previous experience with clinical trials, knowledge about clinical trials, and importance of a comprehensive list of barriers and enablers to trial participation. Participants were contacted by email or through social media. RESULTS: From 2451 subscribers of the CBCN, we received 244 responses and 210 completed surveys (244/2451 or 9.9% participation, 210/244 or 86.1% completion). A total of 38% of respondents indicated experience in trial participation, but 83% indicated confidence in their knowledge about clinical trials. Those who had previously participated in clinical trials were more confident in their knowledge (χ2= 6.77, p = 0.009) and answered more knowledge questions (t = -3.90 p = 0.000). Endorsed barriers and enablers to participation included 39 factors across 12 of 14 domains relevant to behaviour change. Our approach identifies barriers that might be meaningfully addressed by careful knowledge provision ('If I would learn more about my condition'; 'If I find the trial documents hard to understand'), those that may require other theory-informed approaches to address ('my feelings about the quality of my drug plan'; 'my worry over unknown side effects'), and those that may require tailored approaches depending on participant differences such as previous experience in trials ('If there were patient-friendly decision-making tools to help you make your participation decision'). DISCUSSION: This work demonstrates that a comprehensive, theory-guided survey of barriers and enablers to participation in breast cancer clinical trials is feasible, can lead to detailed knowledge about the issues related to participation in specific trials, and most importantly, can lead to insights about evidence-based ways to better support patient participation.

Using behavioral theory and shared decision-making to understand clinical trial recruitment: interviews with trial recruiters.

BACKGROUND: Clinical trial recruitment is a continuing challenge for medical researchers. Previous efforts to improve study recruitment have rarely been informed by theories of human decision making and behavior change. We investigate the trial recruitment strategies reported by study recruiters, guided by two influential theoretical frameworks: shared decision-making (SDM) and the Theoretical Domains Framework (TDF) in order to explore the utility of these frameworks in trial recruitment. METHODS: We interviewed all nine active study recruiters from a multi-site, open-label pilot trial assessing the feasibility of a large-scale randomized trial. Recruiters were primarily nurses or master's-level research assistants with a range of 3 to 30 years of experience. The semi-structured interviews included questions about the typical recruitment encounter, questions concerning the main components of SDM (e.g. verifying understanding, directive vs. non-directive style), and questions investigating the barriers to and drivers of their recruitment activities, based on the TDF. We used directed content analysis to code quotations into TDF domains, followed by inductive thematic analysis to code quotations into sub-themes within domains and overarching themes across TDF domains. Responses to questions related to SDM were aggregated according to level of endorsement and informed the thematic analysis. RESULTS: The analysis helped to identify 28 sub-themes across 11 domains. The sub-themes were organized into six overarching themes: coordinating between people, providing guidance to recruiters about challenges, providing resources to recruiters, optimizing study flow, guiding the recruitment decision, and emphasizing the benefits to participation. The SDM analysis revealed recruiters were able to view recruitment interactions as successful even when enrollment did not proceed, and most recruiters took a non-directive (i.e. providing patients with balanced information on available options) or mixed approach over a directive approach (i.e. focus on enrolling patient in study). Most of the core SDM constructs were frequently endorsed. CONCLUSIONS: Identified sub-themes can be linked to TDF domains for which effective behavior change interventions are known, yielding interventions that can be evaluated as to whether they improve recruitment. Despite having no formal training in shared decision-making, study recruiters reported practices consistent with many elements of SDM. The development of SDM training materials specific to trial recruitment could improve the informed decision-making process for patients.

A review of pragmatic trials found a high degree of diversity in design and scope, deficiencies in reporting and trial registry data, and poor indexing.

OBJECTIVE: We established a large database of trials to serve as a resource for future methodological and ethical analyses. Here, we use meta-data to describe the broad landscape of pragmatic trials including research areas, identification as pragmatic, quality of trial registry data and enrolment. STUDY DESIGN AND SETTING: Trials were identified by a validated search filter and included if a primary report of a health-related randomized trial published January 2014-April 2019. Data were collated from MEDLINE, Web of Science, ClinicalTrials.gov, and full text. RESULTS: 4337 eligible trials were identified from 13,065 records, of which 1988 were registered in ClinicalTrials.gov. Research areas were diverse, with the most common being general and internal medicine; public, environmental and occupational health; and health care sciences and services. The term "pragmatic" was seldom used in titles or abstracts. Several domains in ClinicalTrials.gov had questionable data quality. We estimated that one-fifth of trials under-accrued by at least 15%. CONCLUSION: There is a need to improve reporting of pragmatic trials and quality of trial registry data. Under accrual remains a challenge in pragmatic RCTs despite calls for more streamlined recruitment approaches. The diversity of pragmatic trials should be reflected in future ethical analyses.

Informing the research agenda for optimizing audit and feedback interventions: results of a prioritization exercise.

BACKGROUND: Audit and feedback (A&F) interventions are one of the most common approaches for implementing evidence-based practices. A key barrier to more effective A&F interventions is the lack of a theory-guided approach to the accumulation of evidence. Recent interviews with theory experts identified 313 theory-informed hypotheses, spread across 30 themes, about how to create more effective A&F interventions. In the current survey, we sought to elicit from stakeholders which hypotheses were most likely to advance the field if studied further. METHODS: From the list of 313, three members of the research team identified 216 that were clear and distinguishable enough for prioritization. A web-based survey was then sent to 211 A&F intervention stakeholders asking them to choose up to 50 'priority' hypotheses following the header "A&F interventions will be more effective if…". Analyses included frequencies of endorsement of the individual hypotheses and themes into which they were grouped. RESULTS: 68 of the 211 invited participants responded to the survey. Seven hypotheses were chosen by > 50% of respondents, including A&F interventions will be more effective… "if feedback is provided by a trusted source"; "if recipients are involved in the design/development of the feedback intervention"; "if recommendations related to the feedback are based on good quality evidence"; "if the behaviour is under the control of the recipient"; "if it addresses barriers and facilitators (drivers) to behaviour change"; "if it suggests clear action plans"; and "if target/goal/optimal rates are clear and explicit". The most endorsed theme was Recipient Priorities (four hypotheses were chosen 92 times as a 'priority' hypotheses). CONCLUSIONS: This work determined a set of hypotheses thought by respondents to be to be most likely to advance the field through future A&F intervention research. This work can inform a coordinated research agenda that may more efficiently lead to more effective A&F interventions.

A patient-focused, theory-guided approach to survey design identified barriers to and drivers of clinical trial participation.

OBJECTIVES: Despite clear evidence showing that many clinical trials fail or are delayed because of poor patient recruitment, there is surprisingly little empirically supported guidance for trialists seeking to optimize their trial recruitment strategies. We propose that the challenges of recruitment can be better understood and addressed by thinking of research participation as one or more behaviors, subject to the same forces as other human behaviors. In this article, we describe an adaptable, behavioral theory-driven approach for designing pretrial surveys of the barriers and drivers relevant to trial participation. Instead of proposing a single survey instrument intended to be used uniformly across many situations, we propose that tailored surveys be informed by a common comprehensive, theory-guided development approach that ensures all domains potentially guiding participation are considered. STUDY DESIGN AND SETTING: We used the Theoretical Domains Framework (TDF), which organizes over 100 constructs known to be associated with behavior and behavior change into 14 domains that describe determinants of professional and patient health behaviors, to inform the development of tailored surveys about barriers to and drivers of clinical trial participation. After searching the literature for barriers and drivers to trial recruitment relevant to each of the TDF domains, we developed separate surveys for members of two national health charities (Canadian Breast Cancer Network, Huntington Society of Canada) to exemplify how the approach can be adapted across settings. We conducted think-aloud interviews with members of each group to maximize the clarity and usability of the surveys, elicited opinions about which barriers/drivers were relevant for each patient group, and identified additional barriers/drivers. Interviews proceeded iteratively with changes incorporated into subsequent interviews. Here, we describe our two target patient groups, as well as our process of modifying, adding, and deleting barrier/driver items for each group and across theoretical domains. RESULTS: We interviewed 8 women with a history of breast cancer from the Canadian Breast Cancer Network (48-65 year old) and 11 Huntington Disease community members (9 women) from the Huntington Society of Canada (26-70 year old). After the iterative development interviews, the breast cancer group had identified 38 barriers/drivers thought relevant to their participation in clinical trials across 12 TDF domains. The Huntington group identified 47 items across 13 TDF domains. CONCLUSION: Our patient-focused and theory-guided approach was able to identify a more comprehensive range of barriers to and drivers of trial participation than existing published tools. Our approach is also more broadly adaptable than such tools, in that it uses a theoretical framework and in-depth piloting to generate a set of items tailored to each specific clinical area, rather than a single set of items intended to be applicable to all situations. This theory-guided approach also enables more specific recruitment strategies to be developed once domain-specific barriers are known, potentially optimizing participation for a given trial and helping build a cumulative evidence of barriers/drivers and strategies for addressing them.

Ethical Issues in the Design and Conduct of Pragmatic Cluster Randomized Trials in Hemodialysis Care: An Interview Study With Key Stakeholders.

BACKGROUND: Pragmatic cluster randomized trials (CRTs) offer an opportunity to improve health care by answering important questions about the comparative effectiveness of treatments using a trial design that can be embedded in routine care. There is a lack of empirical research that addresses ethical issues generated by pragmatic CRTs in hemodialysis. OBJECTIVE: To identify stakeholder perceptions of ethical issues in pragmatic CRTs conducted in hemodialysis. DESIGN: Qualitative study using semi-structured interviews. SETTING: In-person or telephone interviews with an international group of stakeholders. PARTICIPANTS: Stakeholders (clinical investigators, methodologists, ethicists and research ethics committee members, and other knowledge users) who had been involved in the design or conduct of a pragmatic individual patient or cluster randomized trial in hemodialysis, or their role would require them to review and evaluate pragmatic CRTs in hemodialysis. METHODS: Interviews were conducted in-person or over the telephone and were audio-recorded with consent. Recorded interviews were transcribed verbatim prior to analysis. Transcripts and field notes were analyzed using a thematic analysis approach. RESULTS: Sixteen interviews were conducted with 19 individuals. Interviewees were largely drawn from North America (84%) and were predominantly clinical investigators (42%). Six themes were identified in which pragmatic CRTs in hemodialysis raise ethical issues: (1) patients treated with hemodialysis as a vulnerable population, (2) appropriate approaches to informed consent, (3) research burdens, (4) roles and responsibilities of gatekeepers, (5) inequities in access to research, and (6) advocacy for patient-centered research and outcomes. LIMITATIONS: Participants were largely from North America and did not include research staff, who may have differing perspectives. CONCLUSIONS: The six themes reflect concerns relating to individual rights, but also the need to consider population-level issues. To date, concerns regarding inequity of access to research and the need for patient-centered research have received less coverage than other, well-known, issues such as consent. Pragmatic CRTs offer a potential approach to address equity concerns and we suggest future ethical analyses and guidance for pragmatic CRTs in hemodialysis embed equity considerations within them. We further note the potential for the co-creation of health data infrastructure with patients which would aid care but also facilitate patient-centered research. These present results will inform planned future guidance in relation to the ethical design and conduct of pragmatic CRTs in hemodialysis. TRIAL REGISTRATION: Registration is not applicable as this is a qualitative study.

CONTEXTE: Les essais pragmatiques randomisés par grappes fournissent une occasion d'améliorer les soins parce qu'ils répondent à des questions importantes sur l'efficacité comparative des traitements en utilisant des modèles pouvant être intégrés aux soins courants. On constate toutefois un manque de recherche empirique abordant les questions éthiques générées par ces essais en contexte d'hémodialyse. OBJECTIF: Connaître le point de vue d'intervenants sur les questions éthiques liées aux essais pragmatiques randomisés par grappes en contexte d'hémodialyse. TYPE D'ÉTUDE: Étude qualitative sous forme d'interviews semi-structurées. CADRE: Interviews téléphoniques ou en personne avec des intervenants internationaux. PARTICIPANTS: Des intervenants (chercheurs cliniciens, spécialistes de la méthodologie, éthiciens, membres de comités d'éthique de la recherche et autres utilisateurs de connaissances) impliqués dans la conception ou la conduite d'essais pragmatiques randomisés menés sur un patient individuel, ou un groupe de patients, en contexte d'hémodialyse; ou des individus dont le rôle pourrait les amener à réviser et à évaluer ce type d'essais cliniques. MÉTHODOLOGIE: Les interviews ont été menées en personne ou au téléphone, et ont été enregistrées avec le consentement des intervenants. Les enregistrements ont été transcrits verbatim pour l'analyse. Les transcriptions et les notes ont été analysées par une approche d'analyse thématique. RÉSULTATS: Seize interviews ont été menées auprès de 19 intervenants, principalement des chercheurs cliniciens (42%) provenant en grande majorité d'Amérique du Nord (84 %). Ces discussions ont dégagé six thèmes pour lesquels les essais pragmatiques randomisés par grappes soulèvent des questions éthiques en contexte d'hémodialyse: 1) les patients hémodialysés en tant que population vulnérable; 2) les approches appropriées en matière de consentement éclairé; 3) la charge de la recherche; 4) les rôles et responsabilités des personnes responsables; 5) les inégalités dans l'accès à la recherche, et; 6) la promotion de la recherche et des résultats axés sur les patients. LIMITES: Les participants provenaient très majoritairement d'Amérique du Nord et aucun membre du personnel de recherche n'a été questionné, ceux-ci auraient pu fournir un point de vue différent. CONCLUSIONS: Les six thèmes rendent compte de préoccupations relatives aux droits individuels, mais indiquent également la nécessité de se pencher sur les enjeux relatifs à la population. À ce jour, les questions concernant l'inégalité dans l'accès à la recherche et la nécessité de faire de la recherche axée sur les patients ont reçu moins d'attention que d'autres enjeux notoires comme le consentement. Les essais pragmatiques randomisés par grappes constituent une approche susceptible d'aborder les questions d'équité; nous suggérons que les futures analyses et orientations éthiques intègrent des considérations d'équité à ce type d'essais en contexte d'hémodialyse. Nous notons également un potentiel pour la co-création d'une infrastructure de données sur la santé avec les patients, ce qui améliorerait les soins tout en facilitant la recherche axée sur les patients. Ces résultats éclaireront les orientations futures pour la conception et la conduite éthique d'essais pragmatiques randomisés par grappes menés en contexte d'hémodialyse.L'enregistrement n'est pas nécessaire puisqu'il s'agit d'une étude qualitative.

Reporting of key methodological and ethical aspects of cluster trials in hemodialysis require improvement: a systematic review.

BACKGROUND: The hemodialysis setting is suitable for trials that use cluster randomization, where intact groups of individuals are randomized. However, cluster randomized trials (CRTs) are complicated in their design, analysis, and reporting and can pose ethical challenges. We reviewed CRTs in the hemodialysis setting with respect to reporting of key methodological and ethical issues. METHODS: We conducted a systematic review of CRTs in the hemodialysis setting, published in English, between 2000 and 2019, and indexed in MEDLINE or Embase. Two reviewers extracted data, and study results were summarized using descriptive statistics. RESULTS: We identified 26 completed CRTs and five study protocols of CRTs. These studies randomized hemodialysis centers (n = 17, 55%), hemodialysis shifts (n = 12, 39%), healthcare providers (n = 1, 3%), and nephrology units (n = 1, 3%). Trials included a median of 28 clusters with a median cluster size of 20 patients. Justification for using a clustered design was provided by 15 trials (48%). Methods that accounted for clustering were used during sample size calculation in 14 (45%), during analyses in 22 (71%), and during both sample size calculation and analyses in 13 trials (42%). Among all CRTs, 26 (84%) reported receiving research ethics committee approval; patient consent was reported in 22 trials: 10 (32%) reported the method of consent for trial participation and 12 (39%) reported no details about how consent was obtained or its purpose. Four trials (13%) reported receiving waivers of consent, and the remaining 5 (16%) provided no or unclear information about the consent process. CONCLUSION: There is an opportunity to improve the conduct and reporting of essential methodological and ethical issues in future CRTs in hemodialysis. REVIEW REGISTRATION: We conducted this systematic review using a pre-specified protocol that was not registered.

Audit and feedback to improve laboratory test and transfusion ordering in critical care: a systematic review.

BACKGROUND: Laboratory tests and transfusions are sometimes ordered inappropriately, particularly in the critical care setting, which sees frequent use of both. Audit and Feedback (A&F) is a potentially useful intervention for modifying healthcare provider behaviors, but its application to the complex, team-based environment of critical care is not well understood. We conducted a systematic review of the literature on A&F interventions for improving test or transfusion ordering in the critical care setting. METHODS: Five databases, two registries, and the bibliographies of relevant articles were searched. We included critical care studies that assessed the use of A&F targeting healthcare provider behaviors, alone or in combination with other interventions to improve test and transfusion ordering, as compared to historical practice, no intervention, or another healthcare behaviour change intervention. Studies were included only if they reported laboratory test or transfusion orders, or the appropriateness of orders, as outcomes. There were no restrictions based on study design, date of publication, or follow-up time. Intervention characteristics and absolute differences in outcomes were summarized. The quality of individual studies was assessed using a modified version of the Effective Practice and Organisation of Care Cochrane Review Group's criteria. RESULTS: We identified 16 studies, including 13 uncontrolled before-after studies, one randomized controlled trial, one controlled before-after study, and one controlled clinical trial (quasi-experimental). These studies described 17 interventions, mostly (88%) multifaceted interventions with an A&F component. Feedback was most often provided in a written format only (41%), more than once (53%), and most often only provided data aggregated to the group-level (41%). Most studies saw a change in the hypothesized direction, but not all studies provided statistical analyses to formally test improvement. Overall study quality was low, with studies often lacking a concurrent control group. CONCLUSIONS: Our review summarizes characteristics of A&F interventions implemented in the critical care context, points to some mechanisms by which A&F might be made more effective in this setting, and provides an overview of how the appropriateness of orders was reported. Our findings suggest that A&F can be effective in the context of critical care; however, further research is required to characterize approaches that optimize the effectiveness in this setting alongside more rigorous evaluation methods. TRIAL REGISTRATION: PROSPERO CRD42016051941.